5-Ht2b receptor antagonists

ABSTRACT

The present invention concerns compounds of formula (I): wherein R 1  is selected from the group consisting of H, and optionally substituted C 1-6  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-4  alkyl, and phenyl-C 1-4  alkyl; R 2  and R 3  are either: (i) independently selected from H, R, R′, SO 2 R, C(═O)R, (CH 2 ) n NR 5 R 6 , where n is from 1 to 4 and R 5  and R 6  are independently selected from H and R, where R is optionally substituted C 1-4  alkyl group, and R′ is an optionally substituted phenyl-C 1-4  alkyl group, or (ii) together with the nitrogen atom to which they are attached, form an optionally substituted C 5-7  heterocyclic group; R 4  is an optionally substituted C 9-14  aryl group; their use as pharmaceuticals, in particular for treating conditions alleviated by antagonism of a 5-HT 2B  receptor.

This invention relates to 5-HT_(2B) receptor antagonists, pharmaceuticalcompositions comprising such compounds, and the use of such compoundsand compositions to treat various diseases.

BACKGROUND OF THE INVENTION

Serotonin, also referred to as 5-hydroxytryptamine (5-HT), is aneurotransmitter with mixed and complex pharmacological characteristics.5-HT acts via a number of discrete 5-HT receptors. Currently, fourteensubtypes of serotonin receptor are recognised and delineated into sevenfamilies, 5-HT₁ to 5-HT₇. Within the 5-HT₂ family, 5-HT_(2A), 5-HT_(2B)and 5-HT_(2C) subtypes are known to exist. The nomenclature andclassification of 5-HT receptors has been reviewed by Martin andHumphrey, Neuropharm., 33, 261-273 (1994) and Hoyer, et al., Pharm.Rev., 46, 157-203 (1994).

There is evidence to suggest a role for 5-HT_(2B) receptors in a numberof medical disorders, and therefore 5-HT_(2B) receptor antagonists arelikely to have a beneficial effect on patients suffering thesedisorders. They include, but are not limited to: disorders of the GItract, and especially disorders involving altered motility, andparticularly irritable bowel syndrome (WO 01/08668); disorders ofgastric motility, dyspepsia, GERD, tachygastria; migraine/neurogenicpain (WO 97/44326); pain (U.S. Pat. No. 5,958,934); anxiety (WO97/44326); depression (WO 97/44326); benign prostatic hyperplasia (U.S.Pat. No. 5,952,331); sleep disorder (WO 97/44326); panic disorder,obsessive compulsive disorder, alcoholism, hypertension, anorexianervosa, and priapism (WO 97/44326); asthma and obstructive airwaydisease (U.S. Pat. No. 5,952,331); incontinence and bladder dysfunction(WO 96/24351); incontinence and bladder dysfunction (WO 96/24351);disorders of the uterus, such as dysmenorrhoea, pre-term labour,post-partum remodelling, endometriosis and fibrosis; pulmonaryhypertension (Launay, J. M., et al., Nature Medicine, 8(10), 1129-1135(2002)).

WO 97/44326 describes aryl pyrimidine derivatives and their use asselective 5-HT_(2B) antagonists. However, although this applicationdiscloses a number of compounds, it is desirable to find further classesof compounds to act as 5-HT_(2B) antagonists, which are preferablyselective against 5-HT_(2A) and 5-HT_(2C) receptors.

SUMMARY OF THE INVENTION

A first aspect of the present invention provides the use of a compoundof formula I:

or a pharmaceutically acceptable salt thereof in the preparation of amedicament for the treatment of a condition alleviated by antagonism ofa 5-HT_(2B) receptor, wherein R¹ is selected from the group consistingof H, and optionally substituted C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, and phenyl-C-₁₋₄ alkyl;

-   -   R² and R³ are either:    -   (i) independently selected from H, R, R′, SO₂R, C(═O)R,        (CH₂)_(n)NR⁵R⁶, where n is from 1 to 4 and R⁵ and R⁶ are        independently selected from H and R, where R is optionally        substituted C₁₋₄ alkyl group, and R′ is an optionally        substituted phenyl-C₁₋₄ alkyl group, or    -   (ii) together with the nitrogen atom to which they are attached,        form an optionally substituted C₅₋₇ heterocyclic group;    -   R⁴ is an optionally substituted C₉₋₁₄ aryl group;    -   provided that when R¹ is H, at least two of the fused rings in        R⁴ are aromatic or only contain carbon ring atoms.

Conditions which can be alleviated by antagonism of a 5-HT_(2B) receptorare discussed above, and particularly include disorders of the GI tract.

A second aspect of the present invention provides a compound of formulaI:

or a pharmaceutically acceptable salt thereof, for use in a method oftherapy, wherein

-   -   R¹ is selected from the group consisting of H, and optionally        substituted C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄        alkyl, and phenyl-C₁₋₄ alkyl;    -   R² and R³ are either:    -   (i) independently selected from H, R, R′, SO₂R, C(═O)R,        (CH₂)_(n)NR⁵R⁶, where n is from 1 to 4 and R⁵ and R⁶ are        independently selected from H and R, where R is a C₁₋₄ alkyl        group optionally substituted by hydroxy, alkoxy and amido, and        R′ is an optionally substituted phenyl-C₁₋₄ alkyl group, or    -   (ii) together with the nitrogen atom to which they are attached,        form an optionally substituted C₅₋₇ heterocyclic group;    -   R⁴ is an optionally substituted C₉₋₁₄ aryl group;    -   provided that when R¹ is H, R² and R³ are independently selected        from H and R, and R⁴ is optionally substituted napth-1-yl.

A third aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of formula I as defined in the secondaspect or a pharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier or diluent.

A fourth aspect of the present invention provides a compound of formulaI:

or a salt, solvate or chemically protected form thereof, wherein

-   -   R¹ is selected from the group consisting of optionally        substituted C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄        alkyl, and phenyl-C₁₋₄ alkyl;    -   R² and R³ are either:    -   (i) independently selected from H, R, R′, SO₂R, C(═O)R,        (CH₂)_(n)NR⁵R⁶, where n is from 1 to 4 and R⁵ and R⁶ are        independently selected from H and R, where R is a C₁₋₄ alkyl        group optionally substituted by hydroxy, alkoxy and amido, and        R′ is an optionally substituted phenyl-C₁₋₄ alkyl group, or    -   (ii) together with the nitrogen atom to which they are attached,        form an optionally substituted C₅₋₇ heterocyclic group;    -   R⁴ is an optionally substituted C₉₋₁₄ aryl group

Another aspect of the present invention provides a method of treating acondition which can be alleviated by antagonism of a 5-HT_(2B) receptor,which method comprises administering to a patient in need of treatmentan effective amount of a compound of formula I as described in the firstaspect of the invention, or a pharmaceutically acceptable salt thereof.

It is preferred that the compounds described above are selective asagainst 5-HT_(2A) and 5-HT_(2C) receptors.

DEFINITIONS

C₁₋₆ alkyl group: The term “C₁₋₆ alkyl”, as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from a carbonatom of a non-cyclic hydrocarbon compound having from 1 to 6 carbonatoms, and which may be saturated or unsaturated.

Examples of saturated C₁₋₆ alkyl groups include methyl (C₁); ethyl (C₂);propyl (C₃), which may be linear (n-propyl) or branched (iso-propyl);butyl (C₄), which may be linear (n-butyl) or branched (iso-butyl,sec-butyl and tert-butyl); pentyl (C₅), which may be linear (n-pentyl,amyl) or branched (iso-pentyl, neo-pentyl); hexyl (C₆), which may belinear (n-hexyl) or branched.

Examples of unsaturated C₁₋₆ alkyl groups, which may be referred to asC₁₋₆ alkenyl (if they included a double bond) or C₁₋₆ alkynyl (if theyinclude a triple bond) groups, include ethenyl(vinyl, —CH═CH₂),ethynyl(ethinyl, —C≡CH), 1-propenyl(—CH═CH—CH₃), 2-propenyl(allyl,—CH—CH═CH₂), 2-propynyl(propargyl, —CH₂—C≡CH), isopropenyl(—C(CH₃)═CH₂),butenyl (C₄), pentenyl (C₅), and hexenyl (C₆).

C₃₋₇ Cycloalkyl: The term “C₃₋₇ cycloalkyl”, as used herein, pertains toan alkyl group which is also a cyclyl group; that is, a monovalentmoiety obtained by removing a hydrogen atom from an alicyclic ring atomof a cyclic hydrocarbon (carbocyclic) compound, which moiety has from 3to 7 ring atoms

Examples of saturated cycloalkyl groups include, but are not limited to,those derived from: cyclopropane (C₃), cyclobutane (C₄), cyclopentane(C₅), cyclohexane (C₆), and cycloheptane (C₇).

Examples of unsaturated cylcoalkyl groups include, but are not limitedto, those derived from: cyclobutene (C₄), cyclopentene (C₅), cyclohexene(C₆), and cycloheptene (C₇).

C₃₋₇ cycloalkyl-C₁₋₄ alkyl: The term “C₃₋₇ cycloalkyl-C₁₋₄ alkyl”, asused herein, pertains to a monovalent moiety obtained by removing ahydrogen atom from a carbon atom of a non-cyclic hydrocarbon compoundhaving from 1 to 4 carbon atoms (C₁₋₄ alkyl), which may be saturated orunsaturated, which itself is substituted by a C₃₋₇ cycloalkyl group.

Examples of C₃₋₇ cycloalkyl-C₁₋₄ alkyl groups include, but are notlimited to, those derived from: cyclohexylethane (C₆-C₂) andcyclopentylpropene (C₅-C₃).

Phenyl-C₁₋₄ alkyl: The term “phenyl-C₁₋₄ alkyl”, as used herein,pertains to a monovalent moiety obtained by removing a hydrogen atomfrom a carbon atom of a non-cyclic hydrocarbon compound having from 1 to4 carbon atoms (C₁₋₄ alkyl), which may be saturated or unsaturated,which itself is substituted by a phenyl group (C₆H₅—).

Examples of phenyl-C₁₋₄ alkyl groups include, but are not limited to,benzyl(phenyl-CH₂—) and those derived from: phenylethane(phenyl-C₂) andphenylpropene(phenyl-C₃).

C₅₋₇ Heterocyclyl: The term “C₅₋₇ heterocyclyl”, as used herein,pertains to a monovalent moiety obtained by removing a hydrogen atomfrom a ring atom of a heterocyclic compound, which moiety has from 5 to7 ring atoms, of which from 1 to 4 are ring heteroatoms. In particular,when R² and R³ together with the nitrogen atom to which they areattached form a C₅₋₇ heterocyclic ring, at least one ring atom will benitrogen.

Examples of C₅₋₇ heterocyclyl groups having at least one nitrogen atom,include, but are not limited to, those derived from:

-   -   N₁: pyrrolidine(tetrahydropyrrole) (C₅), pyrroline (e.g.,        3-pyrroline, 2,5-dihydropyrrole) (C₅), 2H-pyrrole or        3H-pyrrole(isopyrrole, isoazole) (C₅), piperidine (C₆),        dihydropyridine (C₆), tetrahydropyridine (C₆), azepine (C₇);    -   N₂: imidazolidine (C₅), pyrazolidine(diazolidine) (C₅),        imidazoline (C₅), pyrazoline(dihydropyrazole) (C₅), piperazine        (C₆);    -   N₁O₁: tetrahydrooxazole (C₅), dihydrooxazole (C₅),        tetrahydroisoxazole (C₅), dihydroisoxazole (C₅), morpholine        (C₆), tetrahydrooxazine (C₆), dihydrooxazine (C₆), oxazine (C₆);    -   N₁S₁: thiazoline (C₅), thiazolidine (C₅), thiomorpholine (C₆);    -   N₂O₁: oxadiazine (C₆);    -   N₁O₁S₁: oxathiazine (C₆).

C₉₋₁₄ Aryl: The term “C₉₋₁₄ aryl”, as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from an aromaticring atom of an aromatic compound with at least two fused rings, whichmoiety has from 9 to 14 ring atoms. Preferably, each ring has from 5 to7 ring atoms.

The ring atoms may be all carbon atoms, as in “carboaryl groups” (e.g.C₉₋₁₄ carboaryl).

Examples of carboaryl groups include, but are not limited to, thosederived from naphthalene (C₁₀), azulene (C₁₀), anthracene (C₁₄) andphenanthrene (C₁₄).

Examples of aryl groups which comprise fused rings, at least one ofwhich is an aromatic ring, include, but are not limited to, groupsderived from indene (C₉), isoindene (C₉) tetralin (C₁₀) and fluorene(C₁₃).

Alternatively, the ring atoms may include one or more heteroatoms, as in“heteroaryl groups” (e.g. C₉₋₁₄ heteroaryl).

Examples of heteroaryl groups, include, but are not limited to:

-   -   C₉ heteroaryl groups (with 2 fused rings) derived from        benzofuran (O₁), isobenzofuran (O₁), indole (N₁), isoindole        (N₁), indolizine (N₁), indoline (N₁), isoindoline (N₁), purine        (N₄) (e.g. adenine, guanine), benzimidazole (N₂), indazole (N₂),        benzoxazole (N₁O₁), benzisoxazole (N₁O₁), benzodioxole (O₂),        benzofurazan (N₂O₁), benzotriazole (N₃), benzothiophen (S₁),        benzothiazole (N₁S₁), benzothiadiazole (N₂S);    -   C₁₀ heteroaryl groups (with 2 fused rings) derived from chromene        (O₁), isochromene (O₁), chroman (O₁), isochroman (O₁),        benzodioxan (O₂), quinoline (N₁), isoquinoline (N₁), quinolizine        (N₁), benzoxazine (N₁O₁), benzodiazine (N₂), pyridopyridine        (N₂), quinoxaline (N₂), quinazoline (N₂), cinnoline (N₂),        phthalazine (N₂), naphthyridine (N₂), pteridine (N₄);    -   C₁₁ heteroaryl groups (with 2 fused rings) derived from        benzoazepine (N₁), 5-oxa-9-aza-benzocycloheptene (N₁O₁);    -   C₁₃ heteroaryl groups (with 3 fused rings) derived from        carbazole (N₁), dibenzofuran (O₁), dibenzothiophene (S₁),        carboline (N₂), perimidine (N₂), pyridoindole (N₂); and,    -   C₁₄ heteroaryl groups (with 3 fused rings) derived from acridine        (N₁), xanthene (O₁), thioxanthene (S₁), oxanthrene (O₂),        phenoxathiin (O₁S₁), phenazine (N₂), phenoxazine (N₁O₁),        phenothiazine (N₁S₁), thianthrene (S₂), phenanthridine (N₁),        phenanthroline (N₂), phenazine (N₂).

The above described C₉₋₁₄ aryl group includes the radical formed byremoval of a hydrogen atom from any of the possible aromatic ring atoms.The groups formed by this removal can be described by the number of thering atom from which the hydrogen is removed, if there is more than onepossibility. The carboaryl groups derived from, for example, naphthalene(C₁₀) can be either napth-1-yl or nath-2-yl; and from azulene (C₁₀) canbe azul-1-yl, azul-2-yl, azul-4-yl, azul-5-yl and azul-6-yl. Theheteroaryl groups derived, for example, from isoquinoline can beisoquinol-x-yl(x-isoquinolyl), where x can be 1, 3, 4, 5, 6, 7 or 8.

The phrase “optionally substituted”, as used herein, pertains to aparent group, as above, which may be unsubstituted or which may besubstituted by one of the following substituent groups:

C₁₋₂₀ alkyl group: The term “C₁₋₂₀ alkyl”, as used herein, pertains to amonovalent moiety obtained by removing a hydrogen atom from a carbonatom of a hydrocarbon compound having from 1 to 20 carbon atoms (unlessotherwise specified), which may be aliphatic or alicyclic, and which maybe saturated, partially unsaturated, or fully unsaturated. Thus, theterm “alkyl” includes the sub-classes alkenyl, alkynyl and cycloalkyldiscussed below.

In this context, the prefixes (e.g. C₁₋₄, C₁₋₇, C₁₋₂₀, C₂₋₇, C₃₋₇, etc.)denote the number of carbon atoms, or range of number of carbon atoms.For example, the term “C₁₋₄ alkyl,” as used herein, pertains to an alkylgroup having from 1 to 4 carbon atoms. Examples of groups of alkylgroups include C₁₋₄ alkyl (“lower alkyl”), C₁₋₇ alkyl, and C₁₋₂₀ alkyl.

Examples of saturated alkyl groups include, but are not limited to,methyl (C₁), ethyl (C₂), propyl (C₃), butyl (C₄), pentyl (C₅), hexyl(C₆), heptyl (C₇), octyl (C₈), nonyl (C₉), decyl (C₁₀), n-undecyl (C₁₁),dodecyl (C₁₂), tridecyl (C₁₃), tetradecyl (C₁₄), pentadecyl (C₁₅), andeicodecyl (C₂₀).

Examples of saturated linear alkyl groups include, but are not limitedto, methyl (C₁), ethyl (C₂), n-propyl (C₃), n-butyl (C₄), n-pentyl(amyl)(C₅), n-hexyl (C₆), and n-heptyl (C₇) .

Examples of saturated branched alkyl groups include iso-propyl (C₃),iso-butyl (C₄), sec-butyl (C₄), tert-butyl (C₄), iso-pentyl (C₅), andneo-pentyl (C₅) .

Cycloalkyl: The term “cycloalkyl”, as used herein, pertains to an alkylgroup which is also a cyclyl group; that is, a monovalent moietyobtained by removing a hydrogen atom from an alicyclic ring atom of acyclic hydrocarbon (carbocyclic) compound, which moiety has from 3 to 20ring atoms (unless otherwise specified). Preferably, each ring has from3 to 7 ring atoms.

Examples of saturated cycloalkyl groups include, but are not limited to,those derived from: cyclopropane (C₃), cyclobutane (C₄), cyclopentane(C₅), cyclohexane (C₆), cycloheptane (C₇), norbornane (C₇), norpinane(C₇), norcarane (C₇), adamantane (C₁₀), anddecalin(decahydronaphthalene) (C₁₀).

Examples of saturated cycloalkyl groups, which are also referred toherein as “alkyl-cycloalkyl” groups, include, but are not limited to,methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl,dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl,methylcyclohexyl, and dimethylcyclohexyl, menthane, thujane, carane,pinane, bornane, norcarane, and camphene.

Examples of unsaturated cyclic alkenyl groups, which are also referredto herein as “alkyl-cycloalkenyl” groups, include, but are not limitedto, methylcyclopropenyl, dimethylcyclopropenyl, methylcyclobutenyl,dimethylcyclobutenyl, methylcyclopentenyl, dimethylcyclopentenyl,methylcyclohexenyl, and dimethylcyclohexenyl.

Examples of cycloalkyl groups, with one or more other rings fused to theparent cycloalkyl group, include, but are not limited to, those derivedfrom: indene (C₉), indan (e.g., 2,3-dihydro-1H-indene) (C₉),tetraline(1,2,3,4-tetrahydronaphthalene (C₁₀), acenaphthene (C₁₂),fluorene (C₁₃), phenalene (C₁₃), acephenanthrene (C₁₅), aceanthrene(C₁₆). For example, 2H-inden-2-yl is a C₅cycloalkyl group with asubstituent (phenyl) fused thereto.

Alkenyl: The term “alkenyl,” as used herein, pertains to an alkyl grouphaving one or more carbon-carbon double bonds. Examples of groups ofalkenyl groups include C₂₋₄ alkenyl, C₂₋₇ alkenyl, C₂₋₂₀ alkenyl.

Examples of unsaturated alkenyl groups include, but are not limited to,ethenyl(vinyl, —CH═CH₂), 1-propenyl(—CH═CH—CH₃), 2-propenyl(allyl,—CH—CH═CH₂), isopropenyl(—C(CH₃)═CH₂), butenyl (C₄), pentenyl (C₅), andhexenyl (C₆).

Examples of unsaturated cyclic alkenyl groups, which are also referredto herein as “cycloalkenyl” groups, include, but are not limited to,cyclopropenyl (C₃), cyclobutenyl (C₄), cyclopentenyl (C₅), andcyclohexenyl (C₆).

Alkynyl: The term “alkynyl,” as used herein, pertains to an alkyl grouphaving one or more carbon-carbon triple bonds. Examples of groups ofalkynyl groups include C₂₋₄ alkynyl, C₂₋₇ alkynyl, C₂₋₂₀ alkynyl.

Examples of unsaturated alkynyl groups include, but are not limited to,ethynyl(ethinyl, —C≡CH) and 2-propynyl(propargyl, —CH₂—C≡CH).

C₃₋₂₀ heterocyclyl group: The term “C₃₋₂₀ heterocyclyl”, as used herein,pertains to a monovalent moiety obtained by removing a hydrogen atomfrom a ring atom of a heterocyclic compound, which moiety has from 3 to20 ring atoms (unless otherwise specified), of which from 1 to 10 arering heteroatoms. Preferably, each ring has from 3 to 7 ring atoms, ofwhich from 1 to 4 are ring heteroatoms.

In this context, the prefixes (e.g. C₃₋₂₀, C₃₋₇, C₅₋₆, etc.) denote thenumber of ring atoms, or range of number of ring atoms, whether carbonatoms or heteroatoms. For example, the term “C₅₋₆ heterocyclyl,” as usedherein, pertains to a heterocyclyl group having 5 or 6 ring atoms.Examples of groups of heterocyclyl groups include C₃₋₂₀ heterocyclyl,C₃₋₇ heterocyclyl, C₅₋₇ heterocyclyl.

Examples of monocyclic heterocyclyl groups include, but are not limitedto, those derived from:

-   -   N₁: aziridine (C₃), azetidine (C₄),        pyrrolidine(tetrahydropyrrole) (C₅), pyrroline (e.g.,        3-pyrroline, 2,5-dihydropyrrole) (C₅), 2H-pyrrole or        3H-pyrrole(isopyrrole, isoazole) (C₅), piperidine (C₆),        dihydropyridine (C₆), tetrahydropyridine (C₆), azepine (C₇);    -   O₁: oxirane (C₃), oxetane (C₄), oxolane(tetrahydrofuran) (C₅),        oxole(dihydrofuran) (C₅), oxane(tetrahydropyran) (C₆),        dihydropyran (C₆), pyran (C₆), oxepin (C₇);    -   S₁: thiirane (C₃), thietane (C₄), thiolane(tetrahydrothiophene)        (C₅), thiane(tetrahydrothiopyran) (C₆), thiepane (C₇);    -   O₂: dioxolane (C₅), dioxane (C₆), and dioxepane (C₇);    -   O₃: trioxane (C₆);    -   N₂: imidazolidine (C₅), pyrazolidine(diazolidine) (C₅),        imidazoline (C₅), pyrazoline(dihydropyrazole) (C₅), piperazine        (C₆);    -   N₁O₁: tetrahydrooxazole (C₅), dihydrooxazole (C₅),        tetrahydroisoxazole (C₅), dihydroisoxazole (C₅), morpholine        (C₆), tetrahydrooxazine (C₆), dihydrooxazine (C₆), oxazine (C₆);    -   N₁S₁: thiazoline (C₅), thiazolidine (C₅), thiomorpholine (C₆);    -   N₂O₁: oxadiazine (C₆);    -   O₁S₁: oxathiole (C₅) and oxathiane(thioxane) (C₆); and,    -   N₁O₁S₁: oxathiazine (C₆).

Halo: —F, —Cl, —Br, and —I.

Hydroxy: —OH.

Ether: —OR, wherein R is an ether substituent, for example, a C₁₋₇alkylgroup (also referred to as a C₁₋₇alkoxy group, discussed below), aC₃₋₂₀heterocyclyl group (also referred to as a C₃₋₂₀heterocyclyloxygroup), or a C₅₋₂₀aryl group (also referred to as a C₅₋₂₀aryloxy group),preferably a C₁₋₇alkyl group.

C₁₋₇alkoxy: —OR, wherein R is a C₁₋₇alkyl group. Examples of C₁₋₇alkoxygroups include, but are not limited to, —OMe(methoxy), —OEt(ethoxy),—O(nPr)(n-propoxy), −O(iPr)(isopropoxy), —O(nBu)(n-butoxy), —O(sBu)(sec-butoxy), —O(iBu)(isobutoxy), and —O(tBu) (tert-butoxy).

Oxo(keto, -one): ═O.

Thione(thioketone): ═S.

Imino(imine): ═NR, wherein R is an imino substituent, for example,hydrogen, C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably hydrogen or a C₁₋₇alkyl group. Examples of iminogroups include, but are not limited to, ═NH, ═NMe, ═NEt, and ═NPh.

Formyl(carbaldehyde, carboxaldehyde): —C(═O)H.

Acyl(keto): —C(═O)R, wherein R is an acyl substituent, for example, aC₁₋₇alkyl group (also referred to as C₁₋₇alkylacyl or C₁₋₇alkanoyl), aC₃₋₂₀heterocyclyl group (also referred to as C₃₋₂₀heterocyclylacyl), ora C₅₋₂₀aryl group (also referred to as C₅₋₂₀arylacyl), preferably aC₁₋₇alkyl group. Examples of acyl groups include, but are not limitedto, —C(═O)CH₃(acetyl), —C(═O)CH₂CH₃(propionyl),—C(═O)C(CH₃)₃(t-butyryl), and —C(═O)Ph(benzoyl, phenone).

Carboxy(carboxylic acid): —C(═O)OH.

Thiocarboxy(thiocarboxylic acid): —C(═S)SH.

Thiolocarboxy(thiolocarboxylic acid): —C(═O)SH.

Thionocarboxy(thionocarboxylic acid): —C(═S)OH.

Imidic acid: —C(═NH)OH.

Hydroxamic acid: —C(═NOH)OH.

Ester(carboxylate, carboxylic acid ester, oxycarbonyl): —C(═O)OR,wherein R is an ester substituent, for example, a C₁₋₇alkyl group, aC₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇alkylgroup. Examples of ester groups include, but are not limited to,—C(═O)OCH₃, —C(═O)OCH₂CH₃, —C(═O)OC(CH₃)₃, and —C(═O)OPh.

Acyloxy (reverse ester): —OC(═O)R, wherein R is an acyloxy substituent,for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or aC₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples of acyloxygroups include, but are not limited to, —OC(═O)CH₃(acetoxy),—OC(═O)CH₂CH₃, —OC(═O)C(CH₃)₃, —OC(═O)Ph, and —OC(═O)CH₂Ph.

Oxycarboyloxy: —OC(═O)OR, wherein R is an ester substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group. Examples of ester groups include,but are not limited to, —OC(═O)OCH₃, —OC(═O)OCH₂CH₃, —OC(═O)OC(CH₃)₃,and —OC(═O)OPh.

Amido(carbamoyl, carbamyl, aminocarbonyl, carboxamide): —C(═O)NR¹R ,wherein R¹ and R² are independently amino substituents, as defined foramino groups. Examples of amido groups include, but are not limited to,—C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —C(═O)NHCH₂CH₃, and—C(═O)N(CH₂CH₃)₂, as well as amido groups in which R¹ and R², togetherwith the nitrogen atom to which they are attached, form a heterocyclicstructure as in, for example, piperidinocarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl, and piperazinocarbonyl.

Acylamido(acylamino): —NR¹C(═O)R², wherein R¹ is an amide substituent,for example, hydrogen, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, ora C₅₋₂₀aryl group, preferably hydrogen or a C₁₋₇alkyl group, and R² isan acyl substituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclylgroup, or a C₅₋₂₀aryl group, preferably hydrogen or a C₁₋₇alkyl group.Examples of acylamide groups include, but are not limited to,—NHC(═O)CH₃, —NHC(═O)CH₂CH₃, and —NHC(═O)Ph. R¹ and R² may together forma cyclic structure, as in, for example, succinimidyl, maleimidyl, andphthalimidyl:

Thioamido(thiocarbamyl): —C(═S)NR¹R², wherein R¹ and R² areindependently amino substituents, as defined for amino groups. Examplesof thioamido groups include, but are not limited to, —C(═S)NH₂,—C(═S)NHCH₃, —C(═S)N(CH₃)₂, and —C(═S)NHCH₂CH₃.

Ureido: —N(R¹)CONR²R³ wherein R² and R³ are independently aminosubstituents, as defined for amino groups, and R¹ is a ureidosubstituent, for example, hydrogen, a C₁₋₇alkyl group, aC₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably hydrogen or aC₁₋₇alkyl group. Examples of ureido groups include, but are not limitedto, —NHCONH₂, —NHCONHMe, —NHCONHEt, —NHCONMe₂, —NHCONEt₂, —NMeCONH₂,—NMeCONHMe, —NMeCONHEt, —NMeCONMe₂, and —NMeCONEt₂.

Guanidino: —NH—C(═NH)NH₂.

Tetrazolyl: a five membered aromatic ring having four nitrogen atoms andone carbon atom,

Amino: —NR¹R², wherein R¹ and R² are independently amino substituents,for example, hydrogen, a C₁₋₇alkyl group (also referred to asC₁₋₇alkylamino or di-C₁₋₇alkylamino), a C₃₋₂₀heterocyclyl group, or aC₅₋₂₀aryl group, preferably H or a C₁₋₇alkyl group, or, in the case of a“cyclic” amino group, R¹ and R², taken together with the nitrogen atomto which they are attached, form a heterocyclic ring having from 4 to 8ring atoms. Amino groups may be primary (—NH₂), secondary (—NHR¹), ortertiary (—NHR¹R²), and in cationic form, may be quaternary (—⁺NR¹R²R³).Examples of amino groups include, but are not limited to, —NH₂, —NHCH₃,—NHC(CH₃)₂, —N(CH₃)₂, —N(CH₂CH₃)₂, and —NHPh. Examples of cyclic aminogroups include, but are not limited to, aziridino, azetidino,pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino.

Amidine(amidino): —C(═NR)NR₂, wherein each R is an amidine substituent,for example, hydrogen, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, ora C₅₋₂₀aryl group, preferably H or a C₁₋₇alkyl group. Examples ofamidine groups include, but are not limited to, —C(═NH)NH₂, —C(═NH)NMe₂,and —C(═NMe)NMe₂.

Nitro: —NO₂.

Nitroso: —NO.

Cyano(nitrile, carbonitrile): —CN.

Sulfhydryl(thiol, mercapto): —SH.

Thioether(sulfide): —SR, wherein R is a thioether substituent, forexample, a C₁₋₇alkyl group (also referred to as a Cl₇alkylthio group), aC₃-₂₀heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇alkylgroup. Examples of C₁₋₇alkylthio groups include, but are not limited to,—SCH₃ and —SCH₂CH₃.

Disulfide: —SS—R, wherein R is a disulfide substituent, for example, aC₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,preferably a C₁₋₇alkyl group (also referred to herein as C₁₋₇alkyldisulfide). Examples of C₁₋₇alkyl disulfide groups include, but are notlimited to, —SSCH₃ and —SSCH₂CH₃.

Sulfine (sulfinyl, sulfoxide): —S(═O)R, wherein R is a sulfinesubstituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group,or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples of sulfinegroups include, but are not limited to, —S(═O)CH₃ and —S(═O)CH₂CH₃.

Sulfone(sulfonyl): —S(═O)₂R, wherein R is a sulfone substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group, including, for example, afluorinated or perfluorinated C₁₋₇alkyl group. Examples of sulfonegroups include, but are not limited to, —S(═O)₂CH₃(methanesulfonyl,mesyl), —S(═O)₂CF₃(triflyl), —S(═O)₂CH₂CH₃(esyl), —S(═O)₂C₄F₉(nonaflyl),—S(═O)₂CH₂CF₃(tresyl), —S(═O)₂CH₂CH₂NH₂(tauryl),—S(═O)₂Ph(phenylsulfonyl, besyl), 4-methylphenylsulfonyl(tosyl),4-chlorophenylsulfonyl(closyl), 4-bromophenylsulfonyl(brosyl),4-nitrophenyl(nosyl), 2-naphthalenesulfonate(napsyl), and5-dimethylamino-naphthalen-1-ylsulfonate(dansyl).

Sulfinic acid(sulfino): —S(═O)OH, —SO₂H.

Sulfonic acid(sulfo): —S(═O)₂OH, —SO₃H.

Sulfinate(sulfinic acid ester): —S(═O)OR; wherein R is a sulfinatesubstituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group,or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples ofsulfinate groups include, but are not limited to,—S(═O)OCH₃(methoxysulfinyl; methyl sulfinate) and—S(═O)OCH₂CH₃(ethoxysulfinyl; ethyl sulfinate).

Sulfonate(sulfonic acid ester): —S(═O)₂OR, wherein R is a sulfonatesubstituent, for example, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group,or a C₅₋₂₀aryl group, preferably a C₁₋₇alkyl group. Examples ofsulfonate groups include, but are not limited to,—S(═O)₂OCH₃(methoxysulfonyl; methyl sulfonate) and—S(═O)₂OCH₂CH₃(ethoxysulfonyl; ethyl sulfonate).

Sulfinyloxy: —OS(=O)R, wherein R is a sulfinyloxy substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group. Examples of sulfinyloxy groupsinclude, but are not limited to, —OS(═O)CH₃ and —OS(═O)CH₂CH₃.

Sulfonyloxy: —OS(═O)₂R, wherein R is a sulfonyloxy substituent, forexample, a C₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀arylgroup, preferably a C₁₋₇alkyl group. Examples of sulfonyloxy groupsinclude, but are not limited to, —OS(═O)₂CH₃(mesylate) and—OS(═O)₂CH₂CH₃(esylate).

Sulfate: —OS(═O)₂OR; wherein R is a sulfate substituent, for example, aC₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,preferably a C₁₋₇alkyl group. Examples of sulfate groups include, butare not limited to, —OS(═O)₂OCH₃ and —SO(═O)₂OCH₂CH₃.

Sulfamyl(sulfamoyl; sulfinic acid amide; sulfinamide): —S(═O)NR¹R²,wherein R¹ and R² are independently amino substituents, as defined foramino groups. Examples of sulfamyl groups include, but are not limitedto, −S(═O)NH₂, —S(═O)NH(CH₃), —S(═O)N(CH₃)₂, —S(═O)NH(CH₂CH₃),—S(═O)N(CH₂CH₃)₂, and —S(═O) NHPh.

Sulfonamido(sulfinamoyl; sulfonic acid amide; sulfonamide):—S(═O)₂NR¹R², wherein R¹ and R² are independently amino substituents, asdefined for amino groups. Examples of sulfonamido groups include, butare not limited to, —S(═O)₂NH₂, —S(═O)₂NH(CH₃), —S(═O)₂N(CH₃)₂,—S(═O)₂NH(CH₂CH₃), —S(═O)₂N(CH₂CH₃)₂, and —S(═O)₂NHPh.

Sulfamino: —NR¹S(═O)₂OH, wherein R¹ is an amino substituent, as definedfor amino groups. Examples of sulfamino groups include, but are notlimited to, —NHS(═O)₂OH and —N(CH₃)S(═O)₂OH.

Sulfonamino: —NR¹S(═O)₂R, wherein R¹ is an amino substituent, as definedfor amino groups, and R is a sulfonamino substituent, for example, aC₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group,preferably a C₁₋₇ alkyl group. Examples of sulfonamino groups include,but are not limited to, —NHS(═O)₂CH₃ and —N(CH₃)S(═O)₂C₆H₅.

Sulfinamino: —NR¹S(═O)R, wherein R¹ is an amino substituent, as definedfor amino groups, and R is a sulfinamino substituent, for example, aC₁₋₇alkyl group, a C₃₋₂₀heterocyclyl group, or a C₅₋₂₀aryl group,preferably a C₁₋₇alkyl group. Examples of sulfinamino groups include,but are not limited to, —NHS(═O)CH₃ and —N(CH₃)S(═O)C₆H₅.

The above listed substituent groups may themselves be furthersubstituted, by one or more of themselves.

Includes Other Forms

Unless otherwise specified, included in the above are the well knownionic, salt, solvate, and protected forms of these substituents. Forexample, a reference to carboxylic acid (—COOH) also includes theanionic (carboxylate) form (—COO⁻), a salt or solvate thereof, as wellas conventional protected forms. Similarly, a reference to an aminogroup includes the protonated form (—N⁺HR¹R²), a salt or solvate of theamino group, for example, a hydrochloride salt, as well as conventionalprotected forms of an amino group. Similarly, a reference to a hydroxylgroup also includes the anionic form (—O⁻), a salt or solvate thereof,as well as conventional protected forms of a hydroxyl group.

Isomers, Salts, Solvates and Protected Forms

Certain compounds may exist in one or more particular geometric,optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric,tautomeric, conformational, or anomeric forms, including but not limitedto, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo-and exo-forms; R—, S—, and meso-forms; D- and L-forms; d- and l-forms;(+) and (−) forms; keto-, enol-, and enolate-forms; syn- and anti-forms;synclinal- and anticlinal-forms; α- and β-forms; axial and equatorialforms; boat-, chair-, twist-, envelope-, and halfchair-forms; andcombinations thereof, hereinafter collectively referred to as “isomers”(or “isomeric forms”)

Note that, except as discussed below for tautomeric forms, specificallyexcluded from the term “isomers,” as used herein, are structural (orconstitutional) isomers (i.e., isomers which differ in the connectionsbetween atoms rather than merely by the position of atoms in space). Forexample, a reference to a methoxy group, —OCH₃, is not to be construedas a reference to its structural isomer, a hydroxymethyl group, —CH₂OH.Similarly, a reference to ortho-chlorophenyl is not to be construed as areference to its structural isomer, meta-chlorophenyl. However, areference to a class of structures may well include structurallyisomeric forms falling within that class (e.g., C₁₋₇alkyl includesn-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl;methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example,keto-, enol-, and enolate-forms, as in, for example, the followingtautomeric pairs: keto/enol (illustrated below), imine/enamine,amide/imino alcohol, amidine/amidine, nitroso/oxime,thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.

Note that specifically included in the term “isomer” are compounds withone or more isotopic substitutions. For example, H may be in anyisotopic form, including ¹H, ²H (D), and ³H (T); C may be in anyisotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopicform, including ¹⁶O and ¹⁸O; and the like.

Unless otherwise specified, a reference to a particular compoundincludes all such isomeric forms, including (wholly or partially)racemic and other mixtures thereof. Methods for the preparation (e.g.,asymmetric synthesis) and separation (e.g., fractional crystallisationand chromatographic means) of such isomeric forms are either known inthe art or are readily obtained by adapting the methods taught herein,or known methods, in a known manner.

Unless otherwise specified, a reference to a particular compound alsoincludes ionic, salt, solvate, and protected forms of thereof, forexample, as discussed below.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding salt of the active compound, for example, apharmaceutically-acceptable salt. Examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19, which isincorporated herein by reference.

For example, if the compound is anionic, or has a functional group whichmay be anionic (e.g., —COOH may be —COO⁻), then a salt may be formedwith a suitable cation. Examples of suitable inorganic cations include,but are not limited to, alkali metal ions such as Na⁺and K⁺, alkalineearth cations such as Ca²⁺and Mg²⁺, and other cations such as Al⁺³.Examples of suitable organic cations include, but are not limited to,ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺,NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺). Examples of some suitable substituted ammoniumions are those derived from: ethylamine, diethylamine,dicyclohexylamine, triethylamine, butylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, benzylamine,phenylbenzylamine, choline, meglumine, and tromethamine, as well asamino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

If the compound is cationic, or has a functional group which may becationic (e.g., —NH₂ may be —NH₃ ⁺), then a salt may be formed with asuitable anion. Examples of suitable inorganic anions include, but arenot limited to, those derived from the following inorganic acids:hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric,nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to,those derived from the following organic acids: 2-acetyoxybenzoic,acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric,edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalenecarboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic,methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic,phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic,succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examplesof suitable polymeric organic anions include, but are not limited to,those derived from the following polymeric acids: tannic acid,carboxymethyl cellulose.

It may be convenient or desirable to prepare, purify, and/or handle acorresponding solvate of the active compound. The term “solvate” is usedherein in the conventional sense to refer to a complex of solute (e.g.,active compound, salt of active compound) and solvent. If the solvent iswater, the solvate may be conveniently referred to as a hydrate, forexample, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

It may be convenient or desirable to prepare, purify, and/or handle theactive compound in a chemically protected form. The term “chemicallyprotected form” is used herein in the conventional chemical sense andpertains to a compound in which one or more reactive functional groupsare protected from undesirable chemical reactions under specifiedconditions (e.g., pH, temperature, radiation, solvent, and the like). Inpractice, well known chemical methods are employed to reversibly renderunreactive a functional group, which otherwise would be reactive, underspecified conditions. In a chemically protected form, one or morereactive functional groups are in the form of a protected or protectinggroup (also known as a masked or masking group or a blocked or blockinggroup). By protecting a reactive functional group, reactions involvingother unprotected reactive functional groups can be performed, withoutaffecting the protected group; the protecting group may be removed,usually in a subsequent step, without substantially affecting theremainder of the molecule. See, for example, Protective Groups inOrganic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley andSons, 1999), which is incorporated herein by reference.

A wide variety of such “protecting”, “blocking”, or “masking” methodsare widely used and well known in organic synthesis. For example, acompound which has two nonequivalent reactive functional groups, both ofwhich would be reactive under specified conditions, may be derivatizedto render one of the functional groups “protected,” and thereforeunreactive, under the specified conditions; so protected, the compoundmay be used as a reactant which has effectively only one reactivefunctional group. After the desired reaction (involving the otherfunctional group) is complete, the protected group may be “deprotected”to return it to its original functionality.

For example, a hydroxy group may be protected as an ether(—OR) or anester(—OC(═O)R), for example, as: a t-butyl ether; a benzyl,benzhydryl(diphenylmethyl), or trityl(triphenylmethyl)ether; atrimethylsilyl or t-butyldimethylsilyl ether; or an acetylester(—OC(═O)CH₃, —OAc).

For example, an aldehyde or ketone group may be protected as anacetal(R—CH(OR)₂) or ketal(R₂C(OR)₂), respectively, in which thecarbonyl group (>C═O) is converted to a diether(>C(OR)₂), by reactionwith, for example, a primary alcohol. The aldehyde or ketone group isreadily regenerated by hydrolysis using a large excess of water in thepresence of acid.

For example, an amine group may be protected, for example, as anamide(—NRCO—R) or a urethane(—NRCO—OR), for example, as: a methylamide(—NHCO—CH₃); a benzyloxy amide(—NHCO—OCH₂C₆H₅, —NH-Cbz); as at-butoxy amide(—NHCO—OC(CH₃)3, —NH-Boc); a 2-biphenyl-2-propoxyamide(—NHCO—OC(CH₃)₂C₆H₄C₆H₅, —NH-Bpoc), as a 9-fluorenylmethoxyamide(−NH-Fmoc), as a 6-nitroveratryloxy amide(—NH-Nvoc), as a2-trimethylsilylethyloxy amide(—NH-Teoc), as a 2,2,2-trichloroethyloxyamide(-NH-Troc), as an allyloxy amide(—NH-Alloc), as a2(-phenylsulfonyl)ethyloxy amide(—NH-Psec); or, in suitable cases (e.g.,cyclic amines), as a nitroxide radical (>N—O.).

For example, a carboxylic acid group may be protected as an ester forexample, as: an C₁₋₇alkyl ester (e.g., a methyl ester; a t-butyl ester);a C₁₋₇haloalkyl ester (e.g., a C₁₋₇trihaloalkyl ester); atriC₁₋₇alkylsilyl-C₁₋₇alkyl ester; or a C₅₋₂₀aryl-C₁₋₇alkyl ester (e.g.,a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as amethyl amide.

For example, a thiol group may be protected as a thioether(—SR), forexample, as: a benzyl thioether; an acetamidomethylether(—S—CH₂NHC(═O)CH₃).

The term “treatment,” as used herein in the context of treating acondition, pertains generally to treatment and therapy, whether of ahuman or an animal (e.g., in veterinary applications), in which somedesired therapeutic effect is achieved, for example, the inhibition ofthe progress of the condition, and includes a reduction in the rate ofprogress, a halt in the rate of progress, amelioration of the condition,and cure of the condition. Treatment as a prophylactic measure (i.e.,prophylaxis) is also included.

The term “therapeutically-effective amount,” as used herein, pertains tothat amount of an active compound, or a material, composition or dosagefrom comprising an active compound, which is effective for producingsome desired therapeutic effect, commensurate with a reasonabletherapeutic effect, commensurate with a reasonable benefit/risk ratio,when administered in accordance with a desired treatment regimen.Suitable dose ranges will typically be in the range of from 0.01 to 20mg/kg/day, preferably from 0.1 to 10 mg/kg/day.

Compositions and their Administration

Compositions may be formulated for any suitable route and means ofadministration. Pharmaceutically acceptable carriers or diluents includethose used in formulations suitable for oral, rectal, nasal, topical(including buccal and sublingual), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural) administration. The formulations may conveniently be presentedin unit dosage form and may be prepared by any of the methods well knownin the art of pharmacy. Such methods include the step of bringing intoassociation the active ingredient with the carrier which constitutes oneor more accessory ingredients. In general the formulations are preparedby uniformly and intimately bringing into association the activeingredient with liquid carriers or finely divided solid carriers orboth, and then, if necessary, shaping the product.

For solid compositions, conventional non-toxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, cellulose,cellulose derivatives, starch, magnesium stearate, sodium saccharin,talcum, glucose, sucrose, magnesium carbonate, and the like may be used.The active compound as defined above may be formulated as suppositoriesusing, for example, polyalkylene glycols, acetylated triglycerides andthe like, as the carrier. Liquid pharmaceutically administrablecompositions can, for example, be prepared by dissolving, dispersing,etc, an active compound as defined above and optional pharmaceuticaladjuvants in a carrier, such as, for example, water, saline aqueousdextrose, glycerol, ethanol, and the like, to thereby form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like, for example, sodium acetate, sorbitan monolaurate,triethanolamine sodium acetate, sorbitan monolaurate, triethanolamineoleate, etc. Actual methods of preparing such dosage forms are known, orwill be apparent, to those skilled in this art; for example, seeRemington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pennsylvania, 15th Edition, 1975. The composition or formulation to beadministered will, in any event, contain a quantity of the activecompound(s) in an amount effective to alleviate the symptoms of thesubject being treated.

Dosage forms or compositions containing active ingredient in the rangeof 0.25 to 95% with the balance made up from non-toxic carrier may beprepared.

For oral administration, a pharmaceutically acceptable non-toxiccomposition is formed by the incorporation of any of the normallyemployed excipients, such as, for example, pharmaceutical grades ofmannitol, lactose, cellulose, cellulose derivatives, sodiumcrosscarmellose, starch, magnesium stearate, sodium saccharin, talcum,glucose, sucrose, magnesium carbonate, and the like. Such compositionstake the form of solutions, suspensions, tablets, pills, capsules,powders, sustained release formulations and the like. Such compositionsmay contain 1%-95% active ingredient, more preferably 2-50%, mostpreferably 5-8%.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol or the like. Inaddition, if desired, the pharmaceutical compositions to be administeredmay also contain minor amounts of non-toxic auxiliary substances such aswetting or emulsifying agents, pH buffering agents and the like, such asfor example, sodium acetate, sorbitan monolaurate, triethanolamineoleate, triethanolamine sodium acetate, etc.

The percentage of active compound contained in such parentalcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject. However,percentages of active ingredient of 0.1% to 10% in solution areemployable, and will be higher if the composition is a solid which willbe subsequently diluted to the above percentages. Preferably, thecomposition will comprise 0.2-2% of the active agent in solution.

Acronyms

For convenience, many chemical moieties are represented using well knownabbreviations, including but not limited to, methyl (Me), ethyl (Et),n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu), sec-butyl (sBu),iso-butyl (iBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex),phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph), methoxy(MeO), ethoxy (EtO), benzoyl (Bz), and acetyl (Ac).

For convenience, many chemical compounds are represented using wellknown abbreviations, including but not limited to, methanol (MeOH),ethanol (EtOH), iso-propanol (i-PrOH), methyl ethyl ketone (MEK), etheror diethyl ether (Et₂O), acetic acid (AcOH), dichloromethane (methylenechloride, DCM), acetonitrile (ACN), trifluoroacetic acid (TFA),dimethylformamide (DMF), tetrahydrofuran (THF), and dimethylsulfoxide(DMSO).

General Synthesis Methods

Compounds according to the present invention can be synthesisedaccording to the following route.

In this method the 2-amino thiazole is produced by the condensation ofthe appropriate α-bromo ketone with an appropriately substitutedthiourea, which reaction is carried out in an organic solvent.

The 5-substituent on the thiazole ring is present in the startingmaterial as the alkyl chain of the α-bromo alkylarylketone, which can beobtained from the parent alkylarylketone if necessary.

The starting ketones for this route are either commercially available oraccessible by, for example, Grignard reactions on the correspondingnitriles or Friedal Crafts reaction of substituted aryls.

A further method of preparing compounds of the present invention is by apalladium catalysed coupling reaction of a 2-amino-4-substitutedthiazole with an aryl boronic acid, or derivative thereof. The4-substituent on the thiazole ring may typically be a halogen, such asbromo, iodo or chloro, or a group such as trifluoromethanesulfonate or aphosphate ester. The aryl boronic acid may also be replaced by certainmagnesium, tin or zinc containing organometallic reagents. For example,a 2-amino-4-bromo-thiazole may be reacted with an aryl boronic acidderivative in an aqueous solvent, for example a mixture of ethanol,water and dimethoxyethane, containing a palladium catalyst such astetrakis(triphenylphosphine)palladium(0) and an inorganic base such assodium carbonate. The reaction is carried out by heating at about 80-90°for several hours.

Alternatively, the boronic acid residue, or equivalent, may be on the4-position of the thiazole ring and the halogen, or equivalent, on thearyl group.

In either of the above routes, any substitution on the aryl group ispreferably present in the relevant starting material, but could beintroduced later in the reaction scheme, with, if necessary, appropriateprotection of other functional groups present in the molecule.

Preferences

The following preferences may be combined with one another, and may bedifferent for each aspect of the present invention.

The optional substituents for R¹, R², R³ and R⁴ are preferablyindependently selected from halo, hydroxy, alkoxy (more preferably C₁₋₄alkoxy), amino (more preferably NH₂, C₁₋₄ alkyl amino, C₁₋₄ dialkylamino), and amido (more preferably CONH₂, C₁₋₄ alkyl amido, C₁₋₄ dialkylamido)

First Aspect

R¹ is preferably selected from H and optionally substituted C₁₋₆ alkyland C₃₋₇ cycloalkyl, more preferably H and optionally substituted C₁₋₆alkyl. Especially preferred are H, and C₁₋₄ alkyl (e.g. methyl,iso-propyl). In some embodiments R¹ may be unsubstituted, but when R¹ issubstituted, preferred substituent groups include halo, hydroxy, andamino.

In some embodiments it is preferred that both R² and R³ are substituted,and in other embodiments that only one or neither of R² and R³ aresubstituted. Each of R² and R³ are preferably independently selectedfrom H, R, R′, where R and R′ are as defined above, and more preferablyselected from H and R. R is preferably an optionally substituted C₁₋₄alkyl group. The preferred substituents for R and R′ include halo,hydroxy, and amino.

It is preferred that all of the fused rings in R⁴ are aromatic or onlycontain only carbon rings atoms (i.e. a carboaryl group).

R⁴ is preferably an optionally substituted C₉₋₁₄ carboaryl group, forexample, naphth-1-yl, naphth-2-yl, anthracen-1-yl, anthracen-2-yl,anthracen-9-yl, phenanthren-1-yl, phenanthren-2-yl, phenanthren-3-yl andphenanthren-4-yl, phenanthren-9-yl. Of these napth-1-yl and napth-2-ylare preferred, with napthy-1-yl being most preferred. Preferredsubstituent groups for R⁴ include halo, hydroxy, amino, amido and C₁₋₄alkyl.

Particularly preferred compounds include:2-amino-5-methyl-4-(naphth-1-yl)thiazole (1),2-amino-5-isopropyl-4-(naphth-1-yl)thiazole (2);2-amino-4-(naphth-1-yl)thiazole (3) and 2-amino-4-(naphth-2-yl)thiazole(4).

Second Aspect

R¹ is preferably selected from H and optionally substituted C₁₋₆ alkyland C₃₋₇ cycloalkyl, more preferably H and optionally substituted C₁₋₆alkyl. Especailly preferred are H, and C₁₋₄ alkyl (e.g. methyl,iso-propyl). In some embodiments R¹ may be unsubstituted, but when R¹ issubstituted, preferred substituent groups include halo, hydroxy, andamino.

In some embodiments it is preferred that both R² and R³ are substituted,and in other embodiments that only one or neither of R² and R³ aresubstituted.

In R² and R³, R is preferably an optionally substituted C₁₋₄ alkylgroup. The preferred substituents for R and R′ include halo, hydroxy,and amino.

Preferred substituent groups for R⁴ include halo, hydroxy, amino, amidoand C₁₋₄ alkyl.

When R¹ is not H, each of R² and R³ are preferably independentlyselected from H, R, R′, where R and R′ are as defined above, and morepreferably selected from H and R.

When R¹ is not H, R⁴ is preferably an optionally substituted C₉₋₁₄carboaryl group, for example, naphth-1-yl, naphth-2-yl, anthracen-1-yl,anthracen-2-yl, anthracen-9-yl, phenanthren-1-yl, phenanthren-2-yl,phenanthren-3-yl and phenanthren-4-yl, phenanthren-9-yl. Of thesenapth-1-yl and napth-2-yl are preferred, with napthy-1-yl being mostpreferred.

Particularly preferred compounds include:2-amino-5-methyl-4-(naphth-1-yl)thiazole (1),2-amino-5-isopropyl-4-(naphth-1-yl)thiazole (2) and2-amino-4-(naphth-1-yl)thiazole (3).

Fourth Aspect

R¹ is preferably selected from optionally substituted C₁₋₆ alkyl andC₃₋₇ cycloalkyl, more preferably optionally substituted C₁₋₆ alkyl.Especailly preferred are C₁₋₄ alkyl (e.g. methyl, iso-propyl). In someembodiments R¹ may be unsubstituted, but when R¹ is substituted,preferred substituent groups include halo, hydroxy, and amino.

In some embodiments it is preferred that both R² and R³ are substituted,and in other embodiments that only one or neither of R² and R³ aresubstituted. Each of R² and R³ are preferably independently selectedfrom H, R, R′, where R and R′ are as defined above, and more preferablyselected from H and R. R is preferably an optionally substituted C₁₋₄alkyl group. The preferred substituents for R and R′ include halo,hydroxy, and amino.

R⁴ is preferably an optionally substituted C₉₋₁₄ carboaryl group, forexample, naphth-1-yl, naphth-2-yl, anthracen-1-yl, anthracen-2-yl,anthracen-9-yl, phenanthren-1-yl, phenanthren-2-yl, phenanthren-3-yl andphenanthren-4-yl, phenanthren-9-yl. Of these napth-1-yl and napth-2-ylare preferred, with napthy-1-yl being most preferred. Preferredsubstituent groups for R⁴ include halo, hydroxy, amino, amido and C₁₋₄alkyl.

Particularly preferred compounds include2-amino-5-methyl-4-(naphth-1-yl)thiazole (1) and2-amino-5-isopropyl-4-(naphth-1-yl)thiazole (2).

Selectivity

The selectivity of the compound for antagonising 5-HT_(2B) receptorsover 5-HT_(2A) and/or 5-HT_(2C) receptors can be quantified by dividingthe Ki for 5-HT_(2B) (see below) by the Ki for 5-HT_(2A/2C) (see below).The resulting ratio is preferably 10 or more, more preferably 100 ormore.

The following examples illustrate the invention.

EXAMPLE 1 Synthesis of 2-amino-5-methyl-4-(naphth-1-yl)thiazole (1)

2-Bromo-1-(naphth-1-yl)-propan-1-one (9.5 g) and thiourea (6.2 g) wereheated to 100° C. in anhydrous toluene (60 ml) for 2 hours. Aftercooling, the mixture was evaporated in vacuo and the residue dissolvedin methanol (40 ml). Dilute hydrochloric acid (0.5M; 250 ml) was addedand the resulting solution was washed twice with ether then basifiedwith sodium hydroxide solution (2M). The mixture was extracted withdichloromethane and chloroform. The combined organic extracts werewashed with water, dried with sodium sulphate, filtered and evaporatedin vacuo. The title compound (1) (4.45 g, m.p. 194-195° C.) was obtainedfollowing re-crystallisation of the residue in ethyl acetate.

¹H NMR (CDCl₃, δ): 2.2 (3H, s); 5.0 (2H, broad s); 7.5 (4H, m); 7.9 (2H,m)

Mass spectrum (m/z): 241 (M+H)⁺

Microanalysis: C, expected 69.97; found 70.86; H, expected 5.03; found5.03; N, expected 11.66; found 11.17;

EXAMPLE 2 Synthesis of 2-amino-5-isopropyl-4-(naphth-1-yl)thiazole (2)

2-Bromo-3-methyl-1-(naphth-1-yl)butan-1-one (4.5g) and thiourea (5.9 g)were heated to 105° C. in anhydrous dimethylformamide (15 ml) for 24hours. After cooling, the mixture was added to sodium bicarbonatesolution and extracted twice with ethyl acetate. The combined organicextracts were washed with water, brine, dried with sodium sulphate,filtered and evaporated in vacuo. The residue was dissolved in ether andextracted twice with hydrochloric acid (2M). The combined aqueousextracts were basified with sodium hydroxide solution (2M) and theresulting mixture was extracted with dichloromethane. The organicextract was dried with sodium sulphate, filtered and evaporated invacuo. The title compound (2) was obtained as a foam (0.18 g) followingsilica gel column chromatography of the residue in 0-1.5% methanol indichloromethane then 33% ethyl acetate in petroleum ether.

¹H NMR (CDCl₃, δ): 1.2 (3H, s); 2.95 (1H, septet); 4.8 (2H, broad s);7.5 (4H, m); 7.9 (3H, m)

Mass spectrum (m/z): 269 (M+H)⁺

Microanalysis: C, expected 71.61; found 71.45; H, expected 6.01; found6.11; N, expected 10.44; found 10.02;

EXAMPLE 3 2-amino-4-(naphth-1-yl)thiazole (3) and2-amino-4-(naphth-2-yl)thiazole (4)

These compounds were obtained from Lancaster Synthesis UK (Morecambe,Lancashire, UK) for testing in the subsequently described assays.

Human Cloned 5-HT_(2B) Receptor Binding Assay

The binding affinity of the compounds for human cloned 5-HT_(2B)receptors was determined using the following assay.

CHO-K1 cells expressing cloned 5-HT_(2B) receptor were maintained inUltra-CHO medium containing 400 μg/ml of G418, 100 U/ml penicillin, 100μg/ml streptomycin, 2.5 μg/ml fungizone and 1% foetal bovine serum, in95/5% O₂/CO₂ at 37° C. The cells were harvested using 0.25% trypsin andwere centrifuged at 800 rpm for 8 minutes. The cells were homogenised in50 mM HEPES buffer containing 1 mM disodium EDTA and 1 mM PMSF at pH7.4, using a Dounce homogeniser (20 strokes). The homogenate wascentrifuged at 2280 rpm (1000 g) and 4° C. for 10 minutes, after whichthe supernatant was removed by decanting. The pellet was re-homogenisedas above, and the resulting supernatant removed and combined with thatalready obtained. The supernatant solution was then centrifuged at 18300rpm (40000 g) for 10 minutes at 4° C. using a Sorvall centrifuge. Thesupernatant was removed, and the pellet was re-suspended in 50 mM bufferat pH 7.4 using a Ultra-turrax T25 Polytron, before centrifugation againat 40000 g as above. This wash procedure was repeated, after which themembrane preparation was stored at a concentration of 1 mg/ml at −80° C.until use.

The membranes were thawed rapidly and diluted in assay buffer containingTris-HCl (50 mM, pH 7.4), ascorbic acid (0.1%) and calcium chloride (4mM). The membranes were homogenised to resuspend them, prior to adding10 or 15 μg of membranes to assay wells containing [³H]LSD (1 nM), assaybuffer (50 mM Tris, 4 mM calcium chloride and 0.1% ascorbic acid)containing pargyline (10 μM), and the test compounds (1×10⁻¹⁰ to 1×10⁻⁴M). Non specific binding was determined in the presence of 100 μM 5-HT.After 30 minutes incubation at 37° C., the assay mixture was filteredthrough a combination of GF-C and GF-B filters, pre-soaked in 1%polyethyleneimine, using a Brandel cell harvester, and were washed threetimes using 50 mM Tris-HCl. Radioactivity retained on the filters wasdetermined by liquid scintillation counting. For each test compound, theconcentration that inhibited binding of [³H)LSD by 50% was determinedusing curve fitting software (Prism). Kd values (concentration of LSDrequired to occupy 50% of the receptor binding sites at equilibrium)determined from saturation binding studies were then used to calculateinhibition dissociation constants (Ki) using the following equation:${Ki} = \frac{{IC}_{50}}{1 + ( \frac{{Radioligand}\quad{concentration}}{{Radioligand}\quad{Kd}} )}$

The results are shown in table 1 below as pKi values. This approachfollows that set out in Kenakin, T. P. Pharmacologic analysis ofdrug-receptor interaction. Raven Press, New York, 2^(nd) Edition, whichis incorporated herein by reference.

Human 5-HT_(2A) and 5-HT_(2C) Receptor Binding Assays

The binding affinity of ligands for human 5-HT_(2A) and 5-HT_(2C)receptors was determined using the following assay. These results werethen used to determine the selectivity of the test compounds for5-HT_(2B) receptors, over 5-HT_(2A) and 5-HT_(2C) receptors.

Membrane preparations from CHO-K1 cells expressing the cloned human5-HT_(2A) receptor were obtained (Euroscreen). The membranes were thawedrapidly and diluted in assay buffer containing Tris-HCl (50 mM, pH 7.7).The membranes were resuspended by homogenisation, prior to adding 15 μgof membranes to assay wells containing [³H] ketanserin (1 nM), assaybuffer (50 mM Tris at pH 7.4) containing pargyline (10 μM), and testcompounds (1×10⁻¹⁰ to 1×10⁻⁴M). Non specific binding was determined inthe presence of 100 μM mianserin. After 15 minutes incubation at 37° C.,the assay mixture was filtered through a combination of GF-C and GF-Bfilters, pre-soaked in 0.05% Brij, using a Brandel cell harvester, andwere washed three times using ice cold Tris-HCl buffer (50 mM).Radioactivity retained on the filters was determined by liquidscintillation counting. For each test compound, the concentration thatinhibited binding of [³H]ketanserin by 50% was determined using curvefitting software (Prism). Kd values (concentration of ketanserinrequired to occupy 50% of the receptor binding sites atequlibrium)determined from saturation binding studies were then used tocalculate inhibition dissociation constants (Ki) using the followingequation:${Ki} = \frac{{IC}_{50}}{1 + ( \frac{{Radioligand}\quad{concentration}}{{Radioligand}\quad{Kd}} )}$

Membrane preparations from CHO-K1 cells expressing the cloned human5-HT_(2C) receptor were obtained (Euroscreen). The membranes were thawedrapidly and diluted in assay buffer containing Tris-HCl (50 mM, pH 7.7),ascorbic acid (0.1%) and pargyline (10 μM). The membranes wereresuspended by homogenisation, prior to adding 6 μg of membranes toassay wells containing [³H] mesulergine (1 nM), assay buffer (50 mM Trisat pH 7.7 and 0.1% ascorbic acid) containing pargyline (10 μM), and testcompounds (1×10⁻¹⁰ to 1×10⁻⁴M). Non specific binding was determined inthe presence of 100 μM mianserin. After 30 minutes incubation at 37° C.,the assay mixture was filtered through a combination of GF-C and GF-Bfilters, pre-soaked in 1% bovine serum albumin, using a Brandel cellharvester, and were washed three times using ice cold Tris-HCl buffer(50 mM). Radioactivity retained on the filters was determined by liquidscintillation counting. For each test compound, the concentration thatinhibited binding of [³H]mesulergine by 50% was determined using curvefitting software (Prism). Kd values (concentration of mesulerginerequired to occupy 50% of the receptor binding sites at equlibrium)determined from saturation binding studies were then used to calculateinhibition dissociation constants (Ki) using the following equation:${Ki} = \frac{{IC}_{50}}{1 + ( \frac{{Radioligand}\quad{concentration}}{{Radioligand}\quad{Kd}} )}$

The results are shown in table 1 below as pKi values. TABLE 1 Compound5-HT_(2B) 5-HT_(2A) 5-HT_(2C) 1 >6 <5 <6 2 >7 <6 <6 3 >6 <6 <6 4 >5 <5<5

Human Cloned 5-HT₂E Cell-Based Functional Assay

The following describes an in vitro functional assay using human cloned5-HT_(2B) receptors to determine the ability of compounds to block thereceptor.

CHO.K1 cells expressing cloned 5-HT_(2B) receptor were maintained InUltra-CHO medium containing 400 μg/ml of G418, 100 U/ml penicillin, 100μg/ml streptomycin, 2.5 μg/ml fungizone, in 95/5% O₂/CO₂ at 37° C.Ultra-CHO medium additionally supplemented with 1% foetal bovine serumwas used when seeding the cells and removed after 5 hours. Cells wereplated in Costar 96 well white, clear-bottomed plate at a density of50,000 cells per well and incubated for at least 24 hours in 95/5%O₂/CO₂ at 37° C. before running the assay.

Media was removed from the wells and 200 μl of 4 μM Fluo-4 AM added,this was incubated in a Wallace Victor 2V workstation at 37° C. for 30minutes. The Fluo-4 AM was then removed from the wells, which were thenwashed twice with 200 μl of buffer (HBSS withoutcalcium/magnesium/phenol red, 20 mM HEPES, 1 mM Ca²⁺, 1 mM Mg²⁺, 2.5 mMprobenecid, pH to 7.4), 180 μl of buffer or test compound was added tothe well and incubated for 30 minutes. The Victor 2V injectors were usedto inject 20 μl of 5-HT after obtaining 10 0.1-second baseline readingsat 535 nm, followed by 150 readings.

All test compounds were aliquoted in 100% DMSO at 10 mM and diluted to 1mM in 50% DMSO, subsequent dilutions were made using buffer. Buffer wasalso used to dilute the 5-HT. Data were analysed using Microsoft Exceland GraphPad Prism, with the latter used to produce sigmoidaldose-response curves for each compound. The compound concentration thatinhibited the 5-HT response by 50% was taken (IC₅₀−M), and the resultsare shown in Table 2, as pIC₅₀, being the negative log (to the base 10)of the measured IC₅₀ values. TABLE 2 Compound pIC₅₀ 1 >6 2 >7 3 >6 4 >5

1. The use of a compound of formula I:

or a pharmaceutically acceptable salt thereof in the preparation of amedicament for the treatment of a condition alleviated by antagonism ofa 5-HT_(2B) receptor, wherein R¹ is selected from the group consistingof H, and optionally substituted C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, and phenyl-C₁₋₄ alkyl; R² and R³ are either: (i)independently selected from H, R, R′, SO₂R, C(═O)R, (CH₂)_(n)NR⁵R⁶,where n is from 1 to 4 and R⁵ and R⁶ are independently selected from Hand R, where R is optionally substituted C₁₋₄ alkyl group, and R′ is anoptionally substituted phenyl-C₁₋₄ alkyl group, or (ii) together withthe nitrogen atom to which they are attached, form an optionallysubstituted C₅₋₇ heterocyclic group; R⁴ is an optionally substitutedC₉₋₁₄ aryl group; provided that when R¹ is H, at least two of the fusedrings in R⁴ are aromatic.
 2. The use according to claim 1, wherein R¹ isselected from H and optionally substituted C₁₋₆ alkyl and C₃₋₇cycloalkyl
 3. The use according to claim 1, wherein R² and R³ areindependently selected from H, R and R′.
 4. The use according to claim1, wherein all of the fused rings in R⁴ are aromatic.
 5. The useaccording to claim 1, wherein R⁴ is an optionally substituted C₉₋₁₄carboaryl group.
 6. The use according to claim 1, wherein R⁴ is anaphthyl group.
 7. The use according to claim 1, wherein the conditionsalleviated by antagonism of a 5-HT_(2B) receptor is a disorder of the GItract.
 8. A compound of formula I:

or a pharmaceutically acceptable salt thereof, for use in a method oftherapy, wherein R¹ is selected from the group consisting of H, C₁₋₆alkyl optionally substituted by halo, hydroxy and amino, optionallysubstituted C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, andphenyl-C-₁₋₄ alkyl; R² and R³ are either: (i) independently selectedfrom H, R, R′, SO₂R, C(═O)R, (CH₂)_(n)NR⁵R⁶, where n is from 1 to 4 andR⁵ and R⁶ are independently selected from H and R, where R is a C₁₋₄alkyl group optionally substituted by hydroxy, alkoxy and amido, and R′is an optionally substituted phenyl-C₁₋₄alkyl group, or (ii) togetherwith the nitrogen atom to which they are attached, form an optionallysubstituted C₅₋₇ heterocyclic group; R⁴ is an optionally substitutedC₉₋₁₄ carboaryl group; provided that when R¹ is H, R² and R³ areindependently selected from H and R, and R⁴ is optionally substitutednapth-1-yl.
 9. The use according to claim 9, wherein R¹ is selected fromH and optionally substituted C₁₋₆ alkyl and C₃₋₇ cycloalkyl
 10. The useaccording to claim 8, wherein in R² and R³, R is an optionallysubstituted C₁₋₄ alkyl group.
 11. The use according to claim 8, whereinR¹ is not H.
 12. The use according to claim 11, wherein R² and R³ areindependently selected from H, R and R′.
 13. The use according to claim11, wherein R⁴ is a napthy-1-yl group.
 14. A pharmaceutical compositioncomprising a compound described in claim 8 or a pharmaceuticallyacceptable salt thereof together with a pharmaceutically acceptablecarrier or diluent.
 15. A compound of formula I:

or a salt, solvate or chemically protected form thereof, wherein R¹ isCH(CH₃)₂; R² and R³ are either: (i) independently selected from H, R,R′, SO₂R, C(═O)R, (CH₂)_(n)NR⁵R⁶ where n is from 1 to 4 and R⁵ and R⁶are independently selected from H and R, where R is a C₁₋₄ alkyl groupoptionally substituted by hydroxy, alkoxy and amido, and R′ is anoptionally substituted phenyl-C₁₋₄ alkyl group, or (ii) together withthe nitrogen atom to which they are attached, form an optionallysubstituted C₅₋₇ heterocyclic group; R⁴ is an optionally substitutedC₉₋₁₄ carboaryl group
 16. A compound according to claim 15, wherein R²and R³ are independently selected from H, R and R′.
 17. A compoundaccording to claim 15, wherein R⁴ is a naphthyl group.
 18. A method oftreating a condition which can be alleviated by antagonism of a5-HT_(2B) receptor, which method comprises administering to a patient inneed of treatment an effective amount of a compound of formula Iaccording to claim 1, or a pharmaceutically acceptable salt thereof.